Journal of Antimicrobial Chemotherapy Advance Access published December 8, 2005

Journal of Antimicrobial Chemotherapy Advance Access published December 8, 2005 Journal of Antimicrobial Chemotherapy doi:10.1093/jac/dki440 An open...
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Journal of Antimicrobial Chemotherapy Advance Access published December 8, 2005

Journal of Antimicrobial Chemotherapy doi:10.1093/jac/dki440

An open-label randomized trial comparing itraconazole oral solution with fluconazole oral solution for primary prophylaxis of fungal infections in patients with haematological malignancy and profound neutropenia Axel Glasmacher1*, Oliver Cornely2, Andrew J. Ullmann3, Ulrich Wedding4, Heinrich Bodenstein5, Hannes Wandt6, Christian Boewer7, Rita Pasold8, Hans-Heinrich Wolf9, Mathias Ha¨nel10, Gottfried Do¨lken11, Christian Junghanss12, Reinhard Andreesen13 and Hartmut Bertz14 on behalf of the Itraconazole Research Group of Germany 1

Department of Internal Medicine I, University of Bonn, Bonn, Germany; 2Department of Internal Medicine I, University of Cologne, Cologne, Germany; 3Department of Internal Medicine III, University of Mainz, Mainz, Germany; 4Department of Internal Medicine II, University of Jena, Jena, Germany; 5Department of Haematology and Oncology, Klinikum Minden, Minden, Germany; 6Department of Internal Medicine V, Klinikum Nu¨rnberg (Nord), Nu¨rnberg, Germany; 7Department of Internal Medicine, St Hedwig Hospital, Berlin, Germany; 8Department of Haematology and Oncology, Klinikum Ernst von Bergmann, Potsdam, Germany; 9Department of Internal Medicine IV, University of Halle, Halle/Saale, Germany; 10Department of Internal Medicine III (Ku¨chwald Hospital), Klinikum Chemnitz, Chemnitz, Germany; 11Department of Internal Medicine C, University of Greifswald, Greifswald, Germany; 12Department of Internal Medicine, Haematology and Oncology, University of Rostock, Rostock, Germany; 13Department of Haematology and Oncology, University of Regensburg, Regensburg, Germany; 14 Department of Internal Medicine, University of Freiburg, Freiburg, Germany Received 6 February 2005; returned 13 April 2005; revised 28 October 2005; accepted 7 November 2005 Objectives: This trial studied the efficacy and safety of itraconazole and fluconazole in the prevention of invasive fungal infections in neutropenic patients with haematological malignancies. Patients and methods: An 8 week, open-label, randomized, parallel-group, multicentre trial comparing itraconazole oral solution (2.5 mg/kg twice daily; N = 248) with fluconazole oral solution or capsules (400 mg daily; N = 246) in 494 patients with anticipated profound neutropenia (i.e. neutrophil count expected to be 90% of all Candida infections.4 In response to these findings, we sought to confirm that antifungal prophylaxis may reduce the morbidity and mortality associated with invasive fungal infections in patients with haematological malignancy and profound neutropenia. The primary objective of this study was to compare the efficacy of itraconazole oral solution with fluconazole oral solution for the prevention of invasive fungal infections, particularly invasive Aspergillus infections, in patients with haematological malignancy and anticipated profound neutropenia (neutrophil count expected to be 56 days. Double asterisks represent as assessed by an independent expert committee.

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Glasmacher et al. amphotericin B; Table 1). There was no significant difference between the two arms in the use of these agents (P = 0.407).

Table 1. Demographic and baseline characteristics

Sex, n (%) male female Age (years), n (%) 16 to 56 days neutropenia No endpoint

Itraconazole 5 mg/kg (N1 = 73) n1 (%) 2 0 1 1 11 0 6 3 2 0 0 11 38 3 8

(2.7) (1.4) (1.4) (15.1) (8.2) (4.1) (2.7)

(15.1) (52.1) (4.1) (11.0)

Fluconazole 400 mg (N2 = 91) n2 (%) 3 1 1 1 14 1 8 4 1 1 1 7 55 4 7

(3.3) (1.1) (1.1) (1.1) (15.4) (1.1) (8.8) (4.4) (1.1) (1.1) (1.1) (7.7) (60.4) (4.4) (7.7)

Total (N = 164) n (%) 5 1 2 2 25 1 14 7 3 1 1 18 93 7 15

(3.0) (0.6) (1.2) (1.2) (15.2) (0.6) (8.5) (4.3) (1.8) (0.6) (0.6) (11.0) (56.7) (4.3) (9.1)

P-valuec 0.839 0.371 0.874 0.874 0.955 0.375 0.916 0.950 NA 0.371 NA 0.137 0.285 0.931 f

Difference in Proportion (%) –0.6 –1.1 0.3 0.3 –0.3 –1.1 –0.6 –0.3 1.6 –1.1 –1.1 7.4 –8.4 –0.3 3.3

95% CId (%) –5.8 –3.2 –3.1 –3.1 –11.4 –3.2 –9.1 –6.5 –2.7 –3.2 –3.2 –2.5 –23.6 –6.5 –5.8

CI, confidence interval; NA, not applicable. a Intent-to-treat patients with neutrophil count less than 500 cells/mm3 for at least 10 consecutive days. b Endpoints were based on a review by an expert panel. c Between-treatment P value from Cochran–Mantel–Haenszel test controlling for underlying disease (acute leukaemia and others). d 95% CI of the difference in proportion = difference in proportion – 1.96 * [p1 * (1 – p1)/N1 + p2 * (1 – p2)/N2]1/2, where p1 = n1/N1 and p2 = n2/N2. e Requiring systemic antifungal therapy. f P-value for ‘no endpoint’ not available because Breslow-Day test for homogeneity of the odds ratio was significant.

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to to to to to to to to to to to to to to to

4.7 1.0 3.7 3.7 10.7 1.0 8.0 5.9 6.0 1.0 1.0 17.2 6.9 5.9 12.3

Glasmacher et al. Table 4. Summary of mortality

Intent-to-treat population Mortality from proven invasive fungal infection Mortality from any cause

Profoundly neutropenic population Mortality from proven invasive fungal infection Mortality from any cause

P-valuea

Difference in proportion (%)

95% CIb (%)

5 (1.0)

0.628

–0.4

–2.2 to 1.4

28 (11.4)

53 (10.7)

0.678

–1.3

–6.8 to 4.2

(N2 = 91) n2 (%)

(N = 164) n (%)

3 (3.3)

3 (1.8)

0.119

–3.3

–7.0 to 0.4

13 (14.3)

18 (11.0)

0.128

–7.4

–16.7 to 1.8

Itraconazole 5 mg/kg

Fluconazole 400 mg

Total

(N1 = 248) n1 (%)

(N2 = 246) n2 (%)

(N = 494) n (%)

2 (0.8)

3 (1.2)

25 (10.1) (N1 = 73) n1 (%) c

0 5 (6.8)

CI, confidence interval. a Between-treatment P value from Cochran–Mantel–Haenszel test controlling for underlying disease (acute leukaemia and others). b 95% confidence interval of the difference in proportion = difference in proportion – 1.96 * [p1 * (1 – p1)/N1 + p2*(1 – p2)/N2]1/2, where p1 = n1/N1, and p2 = n2/N2. c Intent-to-treat patients with neutrophil count 500 ng/mL was recommended) can only be reached by application of the oral solution of itraconazole.35 Another alternative is to use intravenous itraconazole as it has been successfully done in two studies in allogeneic stem cell transplantation.14,15 Further research on this problem is clearly needed, unfortunately, pharmacokinetic samples have not been analysed in this study. Pharmacokinetic studies have shown that the use of a loading dose with either oral or intravenous itraconazole achieves effective plasma concentrations faster and more reliably.33–35 No drug-related congestive heart failure or an increase in the rate of sepsis was observed in either arm of this trial, which confirms the results of other clinical studies with itraconazole and fluconazole.10,38 In conclusion, owing to the low number of proven invasive fungal infections, the sensitivity of this study was not sufficient to demonstrate a difference between itraconazole and fluconazole in the antifungal prophylaxis in neutropenic patients. Additionally, this trial provides evidence for the equivalent safety of itraconazole and fluconazole in this indication.

Acknowledgements Draft manuscript was prepared in part by Sean O’Connell, PharmaNet, for a fee. Assistance with preparation and review of the manuscript were provided by Cynthia Fowler, MD; Helle Gawrylewski, MA and Karyn Fountaine (J&J Pharmaceutical Research & Development, Raritan, NJ, USA). The members of the expert committee were Dr D. Berger (Freiburg, Principal Investigator), Dr C. Heußel (Mainz, radiologist), Dr J. Maertens (Leuven, haematologist), J. Spitz (Clinical Trial Coordinator, Janssen Neuss Germany), W. Seifert (Project Physician, Janssen Beerse Belgium) and E. Everaert (Data Management, Janssen Beerse Belgium). Special acknowledgement to Dr Corinna Hahn-Ast for her very valuable help in the preparation of the manuscript. List of investigators: The Itraconazole Research Group of Germany: Dr A. G., University of Bonn, Bonn; Dr O. A. C., Universita¨t Ko¨ln, Ko¨ln; Dr A. J. U., Universita¨tsklinikum Mainz, Mainz; Prof. Dr Klaus Ho¨ffken and Dr U. W., Klinikum der Friedrich-Schiller-Universita¨t, Jena; Prof. Dr H. B., Klinikum Minden, Minden; Dr H. B., Universita¨tsklinikum Freiburg, Freiburg; Dr H. W., Klinikum Nu¨rnberg Nord, Nu¨rnberg; Dr C. B., St Hedwig Krankenhaus, Berlin; Frau Dr R. P., Klinikum Ernst von Bergmann, Potsdam; Dr H. H. W., Universita¨t Halle, Halle/Saale; Dr M. H., Klinikum Chemnitz, Chemnitz; Prof. Dr G. D., Klinikum der Ernst-Moritz-Arndt-Universita¨t, Greifswald; Prof. Dr M. Freund, Universita¨t Rostock, Rostock; Prof. Dr R. A., Klinikum der Universita¨t Regensburg, Regensburg. Other investigators included: Dr G. Anger, Erfurt; Dr M. Baldus, Ludwigshafen; Dr D. Behringer, Freiburg; Dr D. Berger,

Freiburg; Dr W. Bethge, Tuebingen; Dr M. Boack, Bad Sarrow; Dr F. Boissevain, Nuernberg; Dr F. Breywisch, Potsdam; Dr U. Brockhaus, Potsdam; Dr T. Buechele, Halle; Dr M. Clemens, Trier; Prof. K.-M. Derwahl, Berlin; Dr M. Daskalakis, Freiberg; Dr M. Edinger, Freiberg; Dr H. Einsele, Tuebingen; Dr A. Fauser, Idar Oberstein; Prof. Dr G. Fa¨tkenheuer, Ko¨ln; Dr S. Fetscher, Freiburg; Dr F. Fiedler, Chemnitz; Dr T. Fischer, Mainz; Dr S. Fuchs, Bonn; Dr M. Gnad, Regensburg; Dr B. Goettler, Nuernberg; Dr Grote-Kiehn, Duisburg; Dr Happel, Minden; Dr H. Harder, Regensburg; Dr W. Helbig, Leipzig; Dr A. Hellwig, Dresden; Dr D. Henrig, Ludwigshafen; Dr Hirt, Greifswald; Prof. Dr Chr Huber, Universita¨tsklinikum Mainz, Mainz; Dr U. Hutzschenreuter, Greifswald; Dr P. Immenschuh, Minden; Dr C. Junghanss, Rostock; Dr T. Kiefer, Greifswald; Dr L. Koehler, Ludwigshafen; Dr M. Kropmanns, Potsdam; Dr H. Lampe, Minden; Dr W. Langer, Essen-Werden; Dr A. Liebmann, Leipzig; Dr B. Meuter, Trier; Dr D. Mewes, Ludwigshafen; Dr J. Mezger, Karlsruhe; Prof. Dr R. Mertelsmann, Freiburg; Dr C. Milczynski, Ludwigshafen; Dr M. Moelle, Dresden; Dr B. Oldenkott, Berlin; Dr R. Pahnke, Dortmund; Dr H. Pielken, Dortmund; Dr K. Reuter, Cottbus; Dr A. Richter, Bad Saarow; Dr A. Rost, Darmstadt; Dr F. Rothmmann, Potsdam; Dr M. Rudolphi, Idar Oberstein; Dr J. Saal, Flensburg; Dr K. Schaefer-Eckart, Nuernberg; Prof. Dr H.-J. Schmoll, Halle/Saale; Dr C. Schoeber, Halle; Dr U. Schuler, Dresden; Dr W. Schultze, Bad Saarow; Dr A. Schulze, Erfurt; Dr G. Schwenke, Potsdam; Dr T. Skibbe, Leipzig; Dr A. Spyridonidis, Freiburg; Dr H. Steinhauer, Cottbus; Dr J. Stock, Karlsruhe; Dr M. Teich, Chemnitz; Dr E. Theil, Darmstadt; Dr A. Theis-Menzel, Dortmund; Dr H. Timmer, Dortmund; Dr A. U., Mainz; Dr R. Uebelacker, Wuerzberg; Dr A. Von Poblozki, Halle; Dr S. Weiler, Karlsruhe; Dr M. Westerhausen, Duisburg; Dr M. Wilhelm, Wuerzburg; Dr H. H. Wolf, Halle; Dr H. Wolf, Potsdam; Dr H. Zscherpel, Potsdam. This study was supported in part by grants from Janssen-Cilag, Neuss, Germany.

Transparency declarations All study centres have received support from Janssen-Cilag/ Ortho-Biotech for the conduct of the trial. In addition, the following authors have indicated a financial interest: O. C.: Fujisawa (research support, consultant), Gilead (research support, speaker’s honoraria, consultant), MSD Sharp & Dohme (research support, speaker’s honoraria, consultant), Ortho-Biotech (research support, speaker’s honoraria), Pfizer (research support, speaker’s honoraria, consultant), Schering-Plough (research support, consultant), Vicuron (research support); A. G.: Gilead (speaker’s honoraria), JanssenCilag/Ortho-Biotech (consultant, research support, speaker’s honoraria), MSD Sharp & Dohme (consultant, research support, speaker’s honoraria), Pfizer (research support, speaker’s honoraria), Schering-Plough/Essex (consultant); A. J. U.: Schering-Plough (research support, speaker’s honoraria, consultant), Fujisawa (research support, speaker’s honoraria), MSD (speaker’s honoraria, consultant), Gilead (speaker’s honoraria, consultant), Pfizer (speaker’s honoraria); U. W.: Ortho-Biotech (speaker’s honoraria).

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